Preoperative Chemoradiotherapy for Gastroesophageal Junction Adenocarcinoma Modified by PET/CT: Results of Virtual Planning Study

Background and Objectives: The treatment of gastroesophageal junction (GEJ) adenocarcinoma consists of either perioperative chemotherapy or preoperative chemoradiotherapy. Radiotherapy (RT) in the neoadjuvant setting is associated with a higher probability of resections with negative margins (R0) and better tumor regression rate, which might be enhanced by incrementing RT dose with potential impact on treatment results. This virtual planning study demonstrates the feasibility of increasing the dose to GEJ tumor and involved nodes using PET/CT imaging. Materials and Methods: 16 patients from the chemoradiotherapy arm of the phase II GastroPET study were treated by a prescribed dose of 45.0 Gray (Gy) in 25 fractions. PET/CT was performed before treatment. The prescribed dose was virtually boosted on PET/CT-positive areas to 54.0 Gy by 9 Gy in 5 fractions. Dose-volume histograms (DVH) were compared, and normal tissue complication (NTCP) modeling was performed for both dose schedules. Results: DVHs were exceeded in mean heart dose in one case for 45.0 Gy and two cases for 54.0 Gy, peritoneal space volume criterion V45Gy < 195 ccm in three cases for 54.0 Gy and V15Gy < 825 ccm in one case for both dose schedules. The left lung volume of 25 Gy isodose exceeded 10% in most cases for both schedules. The NTCP values for the heart, spine, liver, kidneys and intestines were zero for both schemes. An increase in NTCP value was for lungs (median 3.15% vs. 4.05% for 25 × 1.8 Gy and 25 + 5 × 1.8 Gy, respectively, p = 0.013) and peritoneal space (median values for 25 × 1.8 Gy and 25 + 5 × 1.8 Gy were 3.3% and 14.25%, respectively, p < 0.001). Conclusion: Boosting PET/CT-positive areas in RT of GEJ tumors is feasible, but prospective trials are needed.

CT-on-Rails versus in-Room CBCT for Online Daily Adaptive Proton Therapy of Head-and-Neck Cancers

Purpose: To compare the efficacy of CT-on-rails versus in-room CBCT for daily adaptive proton therapy. Methods: We analyzed a cohort of ten head-and-neck patients with daily CBCT and corresponding virtual CT images. The necessity of moving the patient after a CT scan is the most significant difference in the adaptation workflow, leading to an increased treatment execution uncertainty σ. It is a combination of the isocenter-matching σi and random patient movements induced by the couch motion σm. The former is assumed to never exceed 1 mm. For the latter, we studied three different scenarios with σm = 1, 2, and 3 mm. Accordingly, to mimic the adaptation workflow with CT-on-rails, we introduced random offsets after Monte-Carlo-based adaptation but before delivery of the adapted plan. Results: There were no significant differences in accumulated dose-volume histograms and dose distributions for σm = 1 and 2 mm. Offsets with σm = 3 mm resulted in underdosage to CTV and hot spots of considerable volume. Conclusion: Since σm typically does not exceed 2 mm for in-room CT, there is no clinically significant dosimetric difference between the two modalities for online adaptive therapy of head-and-neck patients. Therefore, in-room CT-on-rails can be considered a good alternative to CBCT for adaptive proton therapy.

Deep learning-based 3D in vivo dose reconstruction with EPID for MR-LINACs: A proof of concept study

Objective: To develop a novel deep learning-based 3D in vivo dose reconstruction framework with electronic portal imaging device (EPID) for magnetic resonance-linear accelerators (MR-LINACs). Approach: The proposed method directly back-projected 2D portal dose into 3D patient coarse dose, which bypassed the complicated patient-to-EPID scatter estimation step used in conventional methods. A pre-trained convolutional neural network (CNN) was then employed to map the coarse dose to the final accurate dose. The electron return effect caused by the magnetic field was captured with the CNN model. Patient dose and portal dose datasets were synchronously generated with Monte Carlo simulation for 96 patients (78 cases for training and validation and 18 cases for testing) treated with fixed-beam intensity-modulated radiotherapy in four different tumor sites, including the brain, nasopharynx, lung, and rectum. Beam angles from the training dataset were further rotated 2–3 times, and doses were recalculated to augment the datasets. Results: The comparison between reconstructed doses and MC ground truth doses showed mean absolute errors < 0.88% for all tumor sites. The averaged 3D γ-passing rates (3%, 2 mm) were 97.42%±2.66% (brain), 98.53%±0.95% (nasopharynx), 99.41%±0.46% (lung), and 98.63%±1.01% (rectum). The dose volume histograms and indices also showed good consistency. The average dose reconstruction time, including back projection and CNN dose mapping, was less than 3 s for each individual beam. Significance: The proposed method can be potentially used for accurate and fast 3D dosimetric verification for online adaptive radiotherapy using MR-LINACs.

Association Between Brain Substructure Dose and Cognitive Outcomes in Children With Medulloblastoma Treated on SJMB03: A Step Toward Substructure-Informed Planning

PURPOSE To characterize the association between neurocognitive outcomes (memory and processing speed) and radiation (RT) dose to the hippocampus, corpus callosum (CC), and frontal white matter (WM) in children with medulloblastoma treated on a prospective study, SJMB03. PATIENTS AND METHODS Patients age 3-21 years with medulloblastoma were treated at a single institution on a phase III study. The craniospinal RT dose was 23.4 Gy for average-risk patients and 36-39.6 Gy for high-risk patients. The boost dose was 55.8 Gy to the tumor bed. Patients underwent cognitive testing at baseline and once yearly for 5 years. Performance on tests of memory (associative memory and working memory) and processing speed (composite processing speed and perceptual speed) was analyzed. Mixed-effects models were used to estimate longitudinal trends in neurocognitive outcomes. Reliable change index and logistic regression were used to define clinically meaningful neurocognitive decline and identify variables associated with decline. RESULTS One hundred and twenty-four patients were eligible for inclusion, with a median neurocognitive follow-up of 5 years. Mean right and left hippocampal doses were significantly associated with decline in associative memory in patients without posterior fossa syndrome (all P < .05). Mean CC and frontal WM doses were significantly associated with decline in both measures of processing speed (all P < .05). Median brain substructure dose–volume histograms were shifted to the right for patients with a decline in associative memory or processing speed. The odds of decline in associative memory and composite processing speed increased by 23%-26% and by 10%-15% for every 1-Gy increase in mean hippocampal dose and mean CC or frontal WM dose, respectively. CONCLUSION Increasing RT dose to the CC or frontal WM and hippocampus is associated with worse performance on tests of processing speed and associative memory, respectively. Brain substructure–informed RT planning may mitigate neurocognitive impairment.

Impact of different treatment plans on EQD2 for intracavitary brachytherapy of cervical cancer

Background Cancer is one of the leading causes of death worldwide. According to GLOBOCAN estimates, there were 341,831 deaths from cervical cancer in 185 countries in 2020. The aim of this study was to compare equieffective dose (EQD2) at 2 Gy per fraction by using dose volume histograms (DVHs) derived from external beam radiotherapy (EBRT) and high-dose rate brachytherapy (HDR-BRT) treatment plans used in cervical cancer radiotherapy. Methods Fifteen patients with stage IIB-IIIB cervical cancer were included in this retrospective study. Treatment with three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) was planned for all patients in 28 fractions, with a total of 50.4 Gy to be delivered to the whole pelvic region. After EBRT, manual optimization (MO) or inverse optimization (IO) HDR-BRT plans were created in 4 fractions with a total of 28 Gy. The plans obtained were grouped as IMRT + IO, IMRT + MO, 3DCRT + IO, and 3DCRT + MO by calculating EQD2s among these plans. D90, D95, and D98 values were compared in all plans for CTVHR total EQD2. In addition, EQD2 values ​for critical organs at risk (OARs) such as rectum, bladder, small intestine, and sigmoid were compared in all plans for volumes of 2 cm3, 1 cm3, and 0.1 cm3, respectively. Results There was no significant difference between the treatment groups in terms of CTVHR D90 and CTVIR D90 values; However, CTVHR D95 (p = 0.000) and CTVHR D98 (p = 0.000) values ​were found to be better in IMRT + IO technique. The IMRT + IO technique provided better protection for 2 cm3, 1 cm3, and 0.1 cm3 volumes of OARs compared to other techniques. Conclusions Considering all parameters such as CTVHR, CTVIR, rectum, bladder, small intestine, and sigmoid, combination of IMRT + IO treatment option was found to be significantly superior in total EQD2 calculations compared to other plans.

Comparisons of 3-Dimensional Conformal and Intensity-Modulated Neutron Therapy for Head and Neck Cancers

Purpose Neutron therapy is a high linear energy transfer modality that is useful for the treatment of radioresistant head and neck (H&N) cancers. It has been limited to 3-dimensioanal conformal-based fast-neutron therapy (3DCNT), but recent technical advances have enabled the clinical implementation of intensity-modulated neutron therapy (IMNT). This study evaluated the comparative dosimetry of IMNT and 3DCNT plans for the treatment of H&N cancers. Materials and Methods Seven H&N IMNT plans were retrospectively created for patients previously treated with 3DCNT at the University of Washington (Seattle). A custom RayStation model with neutron-specific scattering kernels was used for inverse planning. Organ-at-risk (OAR) objectives from the original 3DCNT plan were initially used and were then systematically reduced to investigate the feasibility of improving a therapeutic ratio, defined as the ratio of the mean tumor to OAR dose. The IMNT and 3DCNT plan quality was evaluated using the therapeutic ratio, isodose contours, and dose volume histograms. Results When compared with the 3DCNT plans, IMNT reduces the OAR dose for the equivalent tumor coverage. Moreover, IMNT is most advantageous for OARs in close spatial proximity to the target. For the 7 patients with H&N cancers examined, the therapeutic ratio for IMNT increased by an average of 56% when compared with the 3DCNT. The maximum OAR dose was reduced by an average of 20.5% and 20.7% for the spinal cord and temporal lobe, respectively. The mean dose to the larynx decreased by an average of 80%. Conclusion The IMNT significantly decreases the OAR doses compared with 3DCNT and provides comparable tumor coverage. Improvements in the therapeutic ratio with IMNT are especially significant for dose-limiting OARs near tumor targets. Moreover, IMNT provides superior sparing of healthy tissues and creates significant new opportunities to improve the care of patients with H&N cancers treated with neutron therapy.

Effective Organs-at-Risk Dose Sparing in Volumetric Modulated Arc Therapy Using a Half-Beam Technique in Whole Pelvic Irradiation

BackgroundAlthough there are some controversies regarding whole pelvic radiation therapy (WPRT) due to its gastrointestinal and hematologic toxicities, it is considered for patients with gynecological, rectal, and prostate cancer. To effectively spare organs-at-risk (OAR) doses using multi-leaf collimator (MLC)’s optimal segments, potential dosimetric benefits in volumetric modulated arc therapy (VMAT) using a half-beam technique (HF) were investigated for WPRT.MethodsWhile the size of a fully opened field (FF) was decided to entirely include a planning target volume in all beam’s eye view across arc angles, the HF was designed to use half the FF from the isocenter for dose optimization. The left or the right half of the FF was alternatively opened in VMAT-HF using a pair of arcs rotating clockwise and counterclockwise. Dosimetric benefits of VMAT-HF, presented with dose conformity, homogeneity, and dose–volume parameters in terms of modulation complex score, were compared to VMAT optimized using the FF (VMAT-FF). Consequent normal tissue complication probability (NTCP) by reducing the irradiated volumes was evaluated as well as dose–volume parameters with statistical analysis for OAR. Moreover, beam-on time and MLC position precision were analyzed with log files to assess plan deliverability and clinical applicability of VMAT-HF as compared to VMAT-FF.ResultsWhile VMAT-HF used 60%–70% less intensity modulation complexity than VMAT-FF, it showed superior dose conformity. The small intestine and colon in VMAT-HF showed a noticeable reduction in the irradiated volumes of up to 35% and 15%, respectively, at an intermediate dose of 20–45 Gy. The small intestine showed statistically significant dose sparing at the volumes that received a dose from 15 to 45 Gy. Such a dose reduction for the small intestine and colon in VMAT-HF presented a significant NTCP reduction from that in VMAT-FF. Without sacrificing the beam delivery efficiency, VMAT-HF achieved effective OAR dose reduction in dose–volume histograms.ConclusionsVMAT-HF led to deliver conformal doses with effective gastrointestinal-OAR dose sparing despite using less modulation complexity. The dose of VMAT-HF was delivered with the same beam-on time with VMAT-FF but precise MLC leaf motions. The VMAT-HF potentially can play a valuable role in reducing OAR toxicities associated with WPRT.

Sarcopenia and dosimetric parameters in relation to treatment-related leukopenia and survival in anal cancer

Background Treatment-related white blood cell (WBC) toxicity has been associated with an inferior prognosis in different malignancies, including anal cancer. The aim of the present study was to investigate predictors of WBC grade ≥ 3 (G3+) toxicity during chemoradiotherapy (CRT) of anal cancer. Methods Consecutive patients with locally advanced (T2 ≥ 4 cm—T4 or N+) anal cancer scheduled for two cycles of concomitant 5-fluorouracil and mitomycin C chemotherapy were selected from an institutional database (n = 106). All received intensity modulated radiotherapy (IMRT; mean dose primary tumor 59.5 Gy; mean dose elective lymph nodes 45.1 Gy). Clinical data were extracted from medical records. The highest-grade WBC toxicity was recorded according to CTCAE version 5.0. Pelvic bone marrow (PBM) was retrospectively contoured and dose-volume histograms were generated. The planning CT was used to measure sarcopenia. Dosimetric, anthropometric, and clinical variables were tested for associations with WBC G3+ toxicity using the Mann–Whitney test and logistic regression. Cox proportional hazard regression was used to assess predictors for overall survival (OS) and anal cancer specific survival (ACSS). Results WBC G3+ was seen in 50.9% of the patients, and 38.7% were sarcopenic. None of the dosimetric parameters showed an association with WBC G3+ toxicity. The most significant predictor of WBC G3+ toxicity was sarcopenia (adjusted OR 4.0; P = 0.002). Sarcopenia was also associated with an inferior OS (adjusted HR 3.9; P = 0.01), but not ACSS (P = 0.07). Sensitivity analysis did not suggest that the inferior prognosis for sarcopenic patients was a consequence of reduced doses of chemotherapy or a prolonged radiation treatment time. Patients who experienced WBC G3+ toxicity had an inferior OS and ACSS, even after adjustment for sarcopenia. Conclusions Sarcopenia was associated with increased risks of both WBC G3+ toxicity and death following CRT for locally advanced anal cancer. In this study, radiation dose to PBM was not associated with WBC G3+ toxicity. However, PBM was not used as an organ at risk for radiotherapy planning purposes and doses to PBM were high, which may have obscured any dose–response relationships.

Yttrium-90 quantitative phantom study using digital photon counting PET

Background PET imaging of 90Y-microsphere distribution following radioembolisation is challenging due to the count-starved statistics from the low branching ratio of e+/e− pair production during 90Y decay. PET systems using silicon photo-multipliers have shown better 90Y image quality compared to conventional photo-multiplier tubes. The main goal of the present study was to evaluate reconstruction parameters for different phantom configurations and varying listmode acquisition lengths to improve quantitative accuracy in 90Y dosimetry, using digital photon counting PET/CT. Methods Quantitative PET and dosimetry accuracy were evaluated using two uniform cylindrical phantoms specific for PET calibration validation. A third body phantom with a 9:1 hot sphere-to-background ratio was scanned at different activity concentrations of 90Y. Reconstructions were performed using OSEM algorithm with varying parameters. Time-of-flight and point-spread function modellings were included in all reconstructions. Absorbed dose calculations were carried out using voxel S-values convolution and were compared to reference Monte Carlo simulations. Dose-volume histograms and root-mean-square deviations were used to evaluate reconstruction parameter sets. Using listmode data, phantom and patient datasets were rebinned into various lengths of time to assess the influence of count statistics on the calculation of absorbed dose. Comparisons between the local energy deposition method and the absorbed dose calculations were performed. Results Using a 2-mm full width at half maximum post-reconstruction Gaussian filter, the dosimetric accuracy was found to be similar to that found with no filter applied but also reduced noise. Larger filter sizes should not be used. An acquisition length of more than 10 min/bed reduces image noise but has no significant impact in the quantification of phantom or patient data for the digital photon counting PET. 3 iterations with 10 subsets were found suitable for large spheres whereas 1 iteration with 30 subsets could improve dosimetry for smaller spheres. Conclusion The best choice of the combination of iterations and subsets depends on the size of the spheres. However, one should be careful on this choice, depending on the imaging conditions and setup. This study can be useful in this choice for future studies for more accurate 90Y post-dosimetry using a digital photon counting PET/CT.

Analysis of the Physical and Radiobiological Equivalence of the Calculated and Measured Dose Distributions for Prostate Stereotactic Radiotherapy

Purpose: Carrying out the analysis of the physical and radiobiological equivalence of dose distributions obtained during the planning of hypofractionated stereotactic radiation therapy of the prostate cancer and verification using a three-dimensional cylindrical dosimeter. Material and Methods: Based on the anatomical data of twelve patients diagnosed with prostate carcinoma, stage T2N0M0 with low risk, plans were developed for stereotactic radiation therapy with volumetric modulates arc therapy (VMAT). The dose per fraction was 7,25 Gy for 5 fractions (total dose 36,25 Gy) with a normal photon energy of 10 MV. The developed plans were verified using a three-dimensional cylindrical ArcCHECK phantom. During the verification process, the three-dimensional dose distribution in the phantom was measured, based on which the values of the three-dimensional gamma index and the dose–volume histogram within each contoured anatomical structures were calculated with 3DVH software. The gamma index value γ (3 %, 2 mm, GN) at a threshold equal to 20 % of the dose maximum of the plan and the percentage of coincidence of points at least 95 % was chosen as a criterion of physical convergence of the calculated and measured dose distribution according to the recommendations of AAPM TG-218. To analyze the radiobiological equivalence of the calculated and measured dose distribution, the local control probability (TCP) and normal tissue complication probability (NTCP) criteria were used based on the calculated and measured dose–volume histograms. Contours of the target (PTV) and the anterior wall of the rectum were used for the analysis. The approach based on the concept of equivalent uniform dose (EUD) by A. Niemierko was used to calculate the values of TCP/NTCP criteria. Results: The results of physical convergence of plans for all patients on the contour of the whole body were higher than 95 % for the criteria γ (3 %, 2 mm, GN). The convergence along the PTV contour is in the range (75.5–95.2)%. The TCP and NTCP values obtained from the measured dose-volume histograms were higher than the planned values for all patients. It was found that the accelerator delivered a slightly higher dose to the PTV and the anterior wall of the rectum than originally planned. Conclusion: The capabilities of modern dosimetric equipment allow us move to the verification of treatment plans based on the analysis of TCP / NTCP radiobiological equivalence, taking into account the individual characteristics of the patient and the capabilities of radiation therapy equipment.